Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

ABSTRACT

The invention relates to pharmaceutical compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. The invention further relates to processes for the preparation of such compositions, and their use in medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/053,511, filed Nov. 6, 2020 which is a 35 U.S.C. § 371 National Stageapplication of International Application PCT/EP2019/061502 (WO2019/215063), filed May 6, 2019, which claims priority to EuropeanPatent Application 18171046.8, filed May 7, 2018; the contents of whichare incorporated herein by reference

TECHNICAL FIELD OF THE INVENTION

The present invention relates to solid compositions comprising a GLP-1agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, theirmethod of preparation and their use in medicine.

INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in XML format via the USPTO patent electronic filing systemand is hereby incorporated by reference in its entirety. Said XML file,created on Nov. 9, 2022, is named 180033US02.xml and is 11 kilobytes insize.

BACKGROUND

Human GLP-1 and analogues thereof have a low oral bioavailability.Exposure and bioavailability of human GLP-1 and analogues thereof isvery low following oral administration. Human GLP-1 and analoguesthereof can only reach therapeutically relevant plasma concentrationafter oral administration if formulated with certain absorptionenhancers in a specific amount.

Steinert et al. (Am J Clin Nutr, October 2010; 92: 810-817) disclosesoral administration of a tablet comprising GLP-1(7-36)amide and 150 mgsodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).

WO 2010/020978 discloses an oral pharmaceutical composition comprising aprotein and N-(8-[2-hydroxybenzoyl) amino)caprylate (SNAC). Patentapplications disclosing oral dosage forms of GLP-1 analogues containinga salt of N-(8-(2-hydroxybenzoyl)amino)caprylate include WO2012/080471,WO2013/189988, WO2013/139694, WO2013/139695 and WO2014/177683.

Despite these findings there is still room for a further optimizedpharmaceutical composition for oral administration of a GLP-1 agonistsuch as a GLP-1 analogue comprising a substituent.

SUMMARY

The present invention in an aspect relates to a composition comprising aGLP-1 agonist, an absorption enhancer or delivery agent and ahydrotrope. The composition according to the invention comprisesbalanced amounts of the delivery agent and the hydrotrope. The providedcompositions display an accelerated absorption, enabling fast andefficient uptake of the active pharmaceutical ingredient.

Oral administration of therapeutic peptides is challenging, due to therapid degradation of such peptides in the gastrointestinal system.

Described herein are pharmaceutical compositions providing accelerateabsorption of the GLP-1 agonist within 15-30 minutes afteradministration and thereby improved exposure of the GLP-1 agonist byoral administration. The inventors have surprisingly found that anincreased exposure of GLP-1 agonists is observed when compositions areprepared with a hydrotrope.

An aspect of the invention relates to a composition comprising

-   -   i) a GLP-1 agonist,    -   ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC)        and    -   iii) a hydrotrope, wherein the hydrotrope is capable of        increasing the solubility of SNAC at least 2-fold, such as        5-fold or such as at least 10-fold.

In one embodiment the composition comprises:

-   -   i) 0.1-50 mg GLP-1 agonist, such as Semaglutide, GLP-1 agonist B        or GLP-1 agonist C.    -   ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (NAC), such as the sodium salt of NAC (SNAC) and    -   iii) 20-200 mg nicotinamide or resorcinol and    -   iv) 0-10 mg lubricant.

A further aspect relates to a method for producing a solidpharmaceutical composition comprising the steps of;

-   -   i) obtaining a blend comprising a salt of NAC and a hydrotrope,    -   ii) co-processing the blend of i) and    -   iii) preparing said solid pharmaceutical composition using the        product of ii).

A further aspect relates to the medical use of compositions describedherein. An embodiment relates to pharmaceutical use of compositionsdescribed herein, such as compositions for oral administration. In afurther embodiment the composition is a pharmaceutical composition foruse in a method of treating diabetes and/or obesity.

In a further aspect the invention relates to a method of treatingdiabetes or obesity comprising administering the composition as definedherein to a patient in need thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows dose dependent effect of nicotinamide (A) and resorcinol(B) on SNAC solubility at pH 6.

FIG. 2 shows the dose corrected exposure during the first 30 minutesobserved in dogs after dosing of formulations with two different GLP-1agonists, GLP-1 agonist A and B, respectively. Compositions according tothe invention all demonstrate an increased dose-corrected exposurerelative to the reference compositions.

DESCRIPTION

Aspects of the invention described herein relate to a compositioncomprising a GLP-1 agonist and an absorption enhancer or delivery agentand a hydrotrope. The composition may be in the form suitable for oraladministration, such as in a solid form exemplified by a tablet, sachetor capsule. In an embodiment the composition is an oral composition, ora pharmaceutical composition, such as an oral pharmaceuticalcomposition. The provided compositions display an acceleratedabsorption, enabling fast and efficient uptake of the activepharmaceutical ingredient.

GLP-1

The term “GLP-1 agonist” as used herein refers to a compound, whichfully or partially activates the human GLP-1 receptor. The term is thusequal to the term “GLP-1 receptor agonist” used in other documents. Theterm GLP-1 agonist as well as the specific GLP-1 agonists describedherein also encompass salt forms thereof.

It follows that the GLP-1 agonist should display “GLP-1 activity” whichrefers to the ability of the compound, i.e. a GLP-1 analogue or acompound comprising a GLP-1 analogue, to bind to the GLP-1 receptor andinitiate a signal transduction pathway resulting in insulinotropicaction or other physiological effects as is known in the art. In someembodiments the “GLP-1 agonist” binds to a GLP-1 receptor, e.g., with anaffinity constant (K_(D)) or activate the receptor with a potency (EC₅₀)of below 1 μM, e.g. below 100 nM as measured by methods known in the art(see e.g. WO 98/08871) and exhibits insulinotropic activity, whereinsulinotropic activity may be measured in vivo or in vitro assays knownto those of ordinary skill in the art. For example, the GLP-1 agonistmay be administered to an animal with increased blood glucose (e.g.obtained using an Intravenous Glucose Tolerance Test (IVGTT). A personskilled in the art will be able to determine a suitable glucose dosageand a suitable blood sampling regime, e.g. depending on the species ofthe animal, for the IVGTT) and measure the plasma insulin concentrationover time. Suitable assays have been described in such as WO2015/155151.

The term half maximal effective concentration (EC₅₀) generally refers tothe concentration which induces a response halfway between the baselineand maximum, by reference to the dose response curve. EC₅₀ is used as ameasure of the potency of a compound and represents the concentrationwhere 50% of its maximal effect is observed. Due to the albumin bindingeffects of GLP-1 agonists comprising a substituent as described herein,it is important to pay attention to if the assay includes human serumalbumin or not.

The in vitro potency of the GLP-1 agonist may be determined as describedin 2015/155151, example 29 without Human Serum Albumin (HSA), and theEC₅₀ determined. The lower the EC₅₀ value, the better the potency. Inone embodiment the potency (EC50) as determined (without HSA) is 5-1000pM, such as 10-750 pM, 10-500 pM or 10-200 pM. In one embodiment theEC50 (without HSA) is at most 500 pM, such as at most 300 pM, such as atmost 200 pM.

In one embodiment the EC50 (without HSA) is comparable to humanGLP-1(7-37).

In one embodiment the EC50 (without HSA) is at most 50 pM. In a furthersuch embodiment the EC50 is at most 40 pM, such as at most 30 pM such asat most 20 pM, such as at most 10 pM. In one embodiment the EC50 isaround 10 pM.

Also, or alternatively, the binding of the GLP-1 agonist to albumin maybe measured using the in vitro potency assay of Example 29 includingHSA. An increase of the in vitro potency, EC₅₀ value, in the presence ofserum albumin reflects the affinity to serum albumin.

In one embodiment the potency (EC50) as determined (with 1% HSA) is5-1000 μM, such as 100-750 pM, 200-500 pM or 100-400 pM. In oneembodiment the EC50 (with 1 HSA) is at most 750 pM, such as at most 500pM, such as at most 400 pM, such as at most 300 or such as at most 250pM.

If desired, the fold variation in relation to a known GLP-1 receptoragonist may be calculated as EC50(test analogue)/EC50(known analogue),and if this ration is such as 0.5-1.5, or 0.8-1.2 the potencies areconsidered to be equivalent.

In one embodiment the potency, EC50 (without HSA), is equivalent to thepotency of liraglutide.

In one embodiment the potency, EC50 (without HSA), is equivalent to thepotency of semaglutide.

In one embodiment the potency, EC50 (without HSA), is equivalent to thepotency of GLP-1 agonist B.

In one embodiment the potency, EC50 (without HSA), is equivalent to thepotency of GLP-1 agonist C.

In one embodiment the potency, EC50 (with 1% HSA), is equivalent to thepotency of liraglutide.

In one embodiment the potency, EC50 (with 1% HSA), is equivalent to thepotency of semaglutide.

In one embodiment the potency, EC50 (with 1% HSA), is equivalent to thepotency of GLP-1 agonist B.

In one embodiment the potency, EC50 (with 1% HSA), is equivalent to thepotency of GLP-1 agonist C.

In one embodiment a GLP-1 agonist is a bifunctional molecule such asco-agonist, or tri-agonist.

In one embodiment the GLP-1 agonist is also a Gastric inhibitorypolypeptide receptor agonist (GIP agonist). In one embodiment the GLP-1agonist is Tirzepatide.

In some embodiments the GLP-1 agonist is a GLP-1 analogue, optionallycomprising one substituent. The term “analogue” as used herein referringto a GLP-1 peptide (hereafter “peptide”) means a peptide wherein atleast one amino acid residue of the peptide has been substituted withanother amino acid residue and/or wherein at least one amino acidresidue has been deleted from the peptide and/or wherein at least oneamino acid residue has been added to the peptide and/or wherein at leastone amino acid residue of the peptide has been modified. Such additionor deletion of amino acid residues may take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide. In some embodimentsa simple nomenclature is used to describe the GLP-1 agonist, e.g.,[Aib8] GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein thenaturally occurring Ala in position 8 has been substituted with Aib. Insome embodiments the GLP-1 agonist comprises a maximum of twelve, suchas a maximum of 10, 8 or 6, amino acids which have been altered, e.g.,by substitution, deletion, insertion and/or modification, compared toe.g. GLP-1(7-37). In some embodiments the analogue comprises up to 10substitutions, deletions, additions and/or insertions, such as up to 9substitutions, deletions, additions and/or insertions, up to 8substitutions, deletions, additions and/or insertions, up to 7substitutions, deletions, additions and/or insertions, up to 6substitutions, deletions, additions and/or insertions, up to 5substitutions, deletions, additions and/or insertions, up to 4substitutions, deletions, additions and/or insertions or up to 3substitutions, deletions, additions and/or insertions, compared to e.g.GLP-1(7-37). Unless otherwise stated the GLP-1 comprises only L-aminoacids.

In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” asused herein refers to a peptide, or a compound, which is a variant ofthe human Glucagon-Like Peptide-1 (GLP-1(7-37)). GLP-1(7-37) has thesequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In someembodiments the term “variant” refers to a compound which comprises oneor more amino acid substitutions, deletions, additions and/orinsertions.

In one embodiment the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%or 90% sequence identity to GLP-1(7-37) over the entire length ofGLP-1(7-37). As an example of a method for determination of sequenceidentity between two analogues the two peptides [Aib8]GLP-1(7-37) andGLP-1(7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37)relative to GLP-1(7-37) is given by the number of aligned identicalresidues minus the number of different residues divided by the totalnumber of residues in GLP-1(7-37). Accordingly, in said example thesequence identity is (31-1)/31.

In one embodiment the C-terminal of the GLP-1 agonist is an amide.

In some embodiments the GLP-1 agonist is GLP-1(7-37) orGLP-1(7-36)amide. In some embodiments the GLP-1 agonist is exendin-4,the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQID No: 2). In one embodiment the GLP-1 agonist is an exendin-4 analogueor an engineered peptide thereof, as disclosed in WO2013009545 andreferences therein.

In order to prolong the effect of the GLP-1 agonist it is preferred thatthe GLP-1 agonist have an extended half-life. The half-life can bedetermined by method known in the art an in an appropriate model, suchas in Male Sprague Dawley rats or minipigs as described inWO2012/140117. Half-life in rats may be determined as in Example 39 andthe half-life in minipigs may be determined as in Example 37 therein.

In one embodiment the GLP-1 agonist according to the invention has ahalf-life above 2 hours in rat. In one embodiment the GLP-1 agonistaccording to the invention has a half-life above 4 hours, such as above6 hours, such as above 8 hours, such as above 10 hours, such as above 12hours or such as above 15 hours in rat.

In one embodiment the GLP-1 agonist according to the invention has ahalf-life above 24 hours in minipig. In one embodiment the GLP-1 agonistaccording to the invention has a half-life above 30 hours, such as above36 hours, such as above 42 hours, such as above 48 hours, such as above54 hours or such as above 60 hours in minipig.

In one embodiment the GLP-1 agonist has a molecular weight of at most 50000 Da, such as at most 40 000 Da, such as at most 30 000 Da.

In one embodiment the GLP-1 agonist has a molecular weight of at most 20000, such as at most 10 000 Da, such as at most 7 500 Da, such as atmost 5 000 Da.

In one embodiment the GLP-1 agonist has a molar mass of at most 50 000g/mol, such as at most 40 000 g/mol, such as at most 30 000 g/mol.

In one embodiment the GLP-1 agonist has a molar mass of at most 10 000g/mol, such as at most 8 000 g/mol, such as at most 6 000 g/mol.

In some embodiments the GLP-1 agonist comprises one substituent which iscovalently attached to the peptide. In some embodiments the substituentcomprises a fatty acid or a fatty diacid. In some embodiments thesubstituent comprises a C16, C18 or C20 fatty acid. In some embodimentsthe substituent comprises a C16, C18 or C20 fatty diacid.

In some embodiments the substituent comprises formula (X)

wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. Insome embodiments the substituent comprises formula (X), wherein n is inthe range of 13 to 19, such as in the range of 13 to 17. In someembodiments the substituent comprises formula (X), wherein n is 13, 15or 17. In some embodiments the substituent comprises formula (X),wherein n is 13. In some embodiments the substituent comprises formula(X), wherein n is 15. In some embodiments the substituent comprisesformula (X), wherein n is 17.

In some embodiments the substituent comprises formula (XIa)

HOOC—(C₆H₄)—O—(CH₂)_(m)—CO—*  (XIa),

wherein m is an integer in the range of 6-14

In some embodiments the substituent comprises formula (XIb)

wherein the carboxy group is in position 2, 3 or 4 of the (C₆H₄) groupand wherein m is an integer in the range of 8-11.

In some embodiments the substituent comprises formula (XIa) or formula(XIb), wherein m is in the range of 6 to 14, such as in the range of 8to 11. In some embodiments the substituent comprises formula (XIa) orformula (XIb), wherein m is 8, 10 or 12. In some embodiments thesubstituent comprises formula (XIa) or formula (XIb), wherein m is 9. Insome embodiments the substituent comprises formula (XIa) or formula(XIb), wherein m is 11.

In some embodiments the substituent comprises one or more8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEG.

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl].

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the GLP-1 agonist is semaglutide, also known asN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),(SEQ ID NO. 4) which may be prepared as described in WO2006/097537,Example 4 with the following structure:

In one embodiment the GLP-1 agonist is GLP-1 agonist B, which isdiacylated [Aib8,Arg34,Lys37]GLP-1(7-37) (SEQ ID NO. 5) as shown inExample 2 of WO2011/080103 and namedN^(ε26){2-[2-(2-{2-[2-(2-{(S)-4-Carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl},N^(ε37)-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}-[Aib⁸,Arg³⁴,Lys³⁷]GLP-1(7-37)-peptidewith the following structure.

In one embodiment the GLP-1 agonist is GLP-1 agonist C which isDiacylated[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly(SEQ ID NO. 6) as shown in Example 31 of WO2012/140117 and namedN^(ε27)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl],N^(ε36)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly with the followingstructure:

In general, the term GLP-1 agonist is meant to encompass the GLP-1agonist and any pharmaceutically acceptable salt, amide, or esterthereof. In some embodiments the composition comprises the GLP-1 agonistor a pharmaceutically acceptable salt, amide, or ester thereof. In someembodiments the composition comprises the GLP-1 agonist and one or morepharmaceutically acceptable counter ions.

In some embodiments the GLP-1 agonist is selected from one or more ofthe GLP-1 agonists mentioned in WO93/19175, WO96/29342, WO98/08871,WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978,WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810,WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050,WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments the GLP-1 agonist is selected from the groupconsisting ofN-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis7, Arg34]GLP-1-(7-37);N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][,DesaminoHis7, Glu22 Arg26, Arg 34,Phe(m-CF3)28]GLP-1-(7-37)amide;N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26]GLP-1(7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino} propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy] acetylamino) ethoxy]ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino} butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy)ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37] GLP-1-(7-37)amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl][DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1-(7-37)-Glu-Lyspeptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyry-lamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26(17-carboxyhepta-decanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide;Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1H(7-37)-OH;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22, Arg34] GLP-1-(7-37);N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26] GLP-1 (7-37)amide;N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);andN-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).

Delivery Agent

A delivery agent or absorption enhancer is for the present invention anexcipient capable of increasing the oral exposure of the GLP-1 agonist.

Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

The delivery agent used in the present invention is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (also referred to herein as asalt of NAC), which contains the anionN-(8-(2-hydroxybenzoyl)amino)caprylate. The structural formula ofN-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (1).

In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid comprises one monovalent cation, two monovalent cations or onedivalent cation. In some embodiments the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the groupconsisting of the sodium salt, potassium salt and/or calcium salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In one embodiment the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidis selected from the group consisting of the sodium salt, potassium saltand/or the ammonium salt. In one embodiment the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt or thepotassium salt. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may beprepared using the method described in e.g. WO96/030036, WO00/046182,WO01/092206 or WO2008/028859.

The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may becrystalline and/or amorphous. In some embodiments the delivery agentcomprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvateor one third of a hydrate of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinationsthereof. In some embodiments the delivery agent is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid as described inWO2007/121318.

In some embodiments the delivery agent is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein),also known as sodium 8-(salicyloylamino)octanoate.

Composition

The composition or pharmaceutical composition of the present inventionis a solid or dry composition suited for administration by the oralroute as described further herein below.

In some embodiments the composition comprises at least onepharmaceutically acceptable excipient. The term “excipient” as usedherein broadly refers to any component other than the active therapeuticingredient(s) or active pharmaceutical ingredient(s) (API(s)). Theexcipient may be a pharmaceutically inert substance, an inactivesubstance, and/or a therapeutically or medicinally none activesubstance.

The excipient may serve various purposes, e.g. as a carrier, vehicle,filler, binder, lubricant, glidant, disintegrant, flow control agent,crystallization inhibitors solubilizer, stabilizer, colouring agent,flavouring agent, surfactant, emulsifier or combinations of thereofand/or to improve administration, and/or absorption of thetherapeutically active substance(s) or active pharmaceuticalingredient(s). The amount of each excipient used may vary within rangesconventional in the art. Techniques and excipients which may be used toformulate oral dosage forms are described in Handbook of PharmaceuticalExcipients, 8th edition, Sheskey et al., Eds., American PharmaceuticalsAssociation and the Pharmaceutical Press, publications department of theRoyal Pharmaceutical Society of Great Britain (2017); and Remington: theScience and Practice of Pharmacy, 22nd edition, Remington and Allen,Eds., Pharmaceutical Press (2013).

In some embodiments the excipients may be selected from binders, such aspolyvinyl pyrrolidone (povidone), etc.; fillers such as cellulosepowder, microcrystalline cellulose, cellulose derivatives likehydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand hydroxy-propylmethylcellulose, dibasic calcium phosphate, cornstarch, pregelatinized starch, etc.; lubricants and/or glidants such asstearic acid, magnesium stearate, sodium stearylfumarate, glyceroltribehenate, etc.; flow control agents such as colloidal silica, talc,etc.; crystallization inhibitors such as Povidone, etc.; solubilizerssuch as Pluronic, Povidone, etc.; colouring agents, including dyes andpigments such as iron oxide red or yellow, titanium dioxide, talc, etc.;pH control agents such as citric acid, tartaric acid, fumaric acid,sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate,etc.; surfactants and emulsifiers such as Pluronic, polyethyleneglycols, sodium carboxymethyl cellulose, polyethoxylated andhydrogenated castor oil, etc.; and mixtures of two or more of theseexcipients and/or adjuvants.

The composition may comprise a binder, such as povidone; starches;celluloses and derivatives thereof, such as microcrystalline cellulose,e.g., Avicel PH from FMC (Philadelphia, Pa.), hydroxypropyl cellulosehydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL fromDow Chemical Corp. (Midland, Mich.); sucrose; dextrose; corn syrup;polysaccharides; and gelatin. The binder may be selected from the groupconsisting of dry binders and/or wet granulation binders. Suitable drybinders are, e.g., cellulose powder and microcrystalline cellulose, suchas Avicel PH 102 and Avicel PH 200. In some embodiments the compositioncomprises Avicel, such as Aavicel PH 102. Suitable binders for wetgranulation or dry granulation are corn starch, polyvinyl pyrrolidone(povidon), vinylpyrrolidone-vinylacetate copolymer (copovidone) andcellulose derivatives like hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose andhydroxyl-propylmethylcellulose. In some embodiments the compositioncomprises povidone.

In some embodiments the composition comprises a filler which may beselected from lactose, mannitol, erythritol, sucrose, sorbitol, calciumphosphate, such as calciumhydrogen phosphate, microcrystallinecellulose, powdered cellulose, confectioner's sugar, compressible sugar,dextrates, dextrin and dextrose. In some embodiments the compositioncomprises microcrystalline cellulose, such as Avicel PH 102 or Avicel PH200.

In some embodiments the composition comprises a lubricant and/or aglidant. In some embodiments the composition comprises a lubricantand/or a glidant, such as talc, magnesium stearate, calcium stearate,zinc stearate, glyceryl behenate, glyceryl debehenate, behenoylpolyoxyl-8 glycerides, polyethylene oxide polymers, sodium laurylsulfate, magnesium lauryl sulfate, sodium oleate, sodium stearylfumarate, stearic acid, hydrogenated vegetable oils, silicon dioxideand/or polyethylene glycol etc. In some embodiments the compositioncomprises magnesium stearate or glyceryl debehenate (such as the productCompritol® 888 ATO).

In some embodiments the composition comprises a disintegrant, such assodium starch glycolate, polacrilin potassium, sodium starch glycolate,crospovidon, croscarmellose, sodium carboxymethylcellulose or dried cornstarch. The composition may comprise one or more surfactants, forexample a surfactant, at least one surfactant, or two differentsurfactants. The term “surfactant” refers to any molecules or ions thatare comprised of a water-soluble (hydrophilic) part, and a fat-soluble(lipophilic) part. The surfactant may e.g. be selected from the groupconsisting of anionic surfactants, cationic surfactants, nonionicsurfactants, and/or zwitterionic surfactants.

Hydrotropes

An aspect of the invention relates to a composition comprising a GLP-1agonist, an absorption enhancer or delivery agent and a hydrotrope. Thecomposition of the present invention further comprises one or morehydrotropes. Hydrotropes like a surfactant includes both a hydrophilicpart and a hydrophobic and can form micelles and self-aggregate, howeverthey solubilize solutes without micellar solubilization. The inventorshave found that that absorption of the GLP-1 agonist and thus the plasmaexposure can be increased by including a hydrotrope in the compositions.Without being bound by theory, it is contemplated that the hydrotropeincreases the solubility of the delivery agent, such as a salt of NAC,as exemplified by SNAC herein. As shown by Assay I herein hydrotropescan increase the solubility of SNAC in water.

In one embodiment the hydrotrope is capable of increasing the solubilityof SNAC. In one embodiment the hydrotrope is capable of increasing thesolubility of a salt of NAC, such as SNAC, at least 2-fold at aconcentration of 200 mg/ml at pH 6 at room temperature. In furtherembodiments, the hydrotrope increases solubility of a salt of NAC, suchas SNAC, at least 3-, 4- or 5-fold when measured as described in Assay Iherein. In a further embodiment, the hydrotrope increase the solubilityof SNAC at least 5-fold, such as 8-fold or such as 10-fold when measuredas described in Assay I.

In one embodiment the hydrotrope or hydrotropes are selected from thegroup consisting of: Nipecotamide, Nicotinamide, p-hydroxybenzoic acidsodium, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethylnicotinamide, Sodium salicylate, Resorcinol, Sodium benzoate, SodiumXylenesulfonate, Sodium p-toluenesulfonate, 1-Methylnicotinamide,Pyrogallol, Pyrocathecol, Epigallocatechin gallate, Tannic acid andGentisic acid sodium salt hydrate.

In one embodiment the hydrotrope or hydrotropes are selected from thegroup consisting of: Nipecotamide, Nicotinamide, p-hydroxybenzoic acidsodium, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethylnicotinamide, Sodium salicylate, Resorcinol, Sodium benzoate, SodiumXylenesulfonate, Sodium p-toluenesulfonate, 1-Methylnicotinamide,Pyrogallol, Pyrocathecol, Epigallocatechin gallate, Tannic acid andGentisic acid sodium salt hydrate.

In one embodiment the hydrotrope or hydrotropes are selected from thegroup consisting of: Nicotinamide, p-hydroxybenzoic acid sodium, N,Ndimethyl urea, N,N dimethyl benzamide, N,N diethyl nicotinamide, Sodiumsalicylate, Resorcinol, Sodium benzoate, Sodium Xylenesulfonate, Sodiump-toluenesulfonate, 1-Methylnicotinamide, Pyrogallol, Pyrocathecol,Epigallocatechin gallate and Gentisic acid sodium salt hydrate.

In one embodiment the hydrotrope or hydrotropes are selected from thegroup consisting of: Nicotinamide, N,N dimethyl benzamide, N,N diethylnicotinamide, Resorcinol, Sodium benzoate, Sodium Xylenesulfonate,Sodium p-toluenesulfonate, 1-Methylnicotinamide, Pyrogallol,Pyrocathecol and Gentisic acid sodium salt hydrate.

In one embodiment the molecular weight of the hydrotrope is at most 400g/mol or such as at most 250 g/mol.

In one embodiment the molecular weight of the hydrotrope is at least 80g/mol or such as at least 100 g/mol

In one embodiment the hydrotrope comprises an aromatic ring structure.

In one embodiment the hydrotrope has a similar molecular structure asnicotinamide and Resorcinol, which both comprises an aromatic ringstructure.

Included herein are also a physiologically acceptable salt thereof, suchas the sodium, potassium, chloride or sulphate salt.

In one embodiment the one or more hydrotrope has the structure of Chem IChem I:

wherein

X is CH or N,

R¹, R² and R³ are independently selected from: —H, —OH, —CO₂H,—CON(R⁴)₂, —SO₃H and —CH₃, wherein R⁴ is —H, —CH₃ or —CH₂—CH₃or a physiologically acceptable salt thereof.

In one embodiment, where the structure is Chem 1,

X is CH or N,

R¹ is selected from —OH, —SO₃H and CON(R⁴)₂, wherein R⁴ is —H, —CH₃ or—CH₂—CH₃,R2 is selected from: —OH and —H andR3 is selected from: —H, —OH and —CH₃ or a physiologically acceptablesalt thereof.

In one embodiment, the hydrotrope has the structure of Chem I, wherein

X is CH,

R1 is selected from: —OH and —SO₃H,R2 and R3 are independently selected from: —H, —OH and —CH₃ or aphysiologically acceptable salt thereof.

In one embodiment the one or more hydrotrope has the structure of ChemII Chem II:

wherein

X is CH or N

R² and R³ are independently selected from: —H, —OH and —CH₃R⁵ is selected from: —OH and N(R⁴)₂, wherein R4 is —H, —CH₃ or —CH₂—CH₃or a physiologically acceptable salt thereof.

In a further embodiment, the one or more hydrotrope has the structure ofChem II wherein,

X is CH R5 is —OH and

R2 and R3 are independently selected from: —OH and —H or aphysiologically acceptable salt thereof.

In a further embodiment, the one or more hydrotrope has the structure ofChem II as defined above, with the proviso that the hydrotrope is notsodium benzoate.

In a further embodiment, the one or more hydrotrope has the structure ofChem II, wherein

X is N,

R⁵ is selected from: —OH and N(R⁴)₂, wherein R4 is —H, —CH₃ or —CH₂—CH₃R² and R³ are independently selected from: —H, —OH and —CH₃ ora physiologically acceptable salt thereof.

In a further embodiment, the one or more hydrotrope has the structure ofChem II, wherein

X is N,

R⁵ is NH₂, andR² and R³ are independently selected from: —H, —OH and —CH₃ ora physiologically acceptable salt thereof.

In one embodiment the one or more hydrotrope has the structure of ChemIII Chem III:

Wherein

R² and R³ are independently selected from —H and —CH₃.

In one embodiment the one or more hydrotrope has the structure of ChemIV Chem IV:

whereinR2 and R3 are independently selected from: —H and —OH.

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Resorcinol, Pyrocatechol, Pyrogallol, Gentisicacid, Xylenesulfonate, p-toluenesulfonate, Nicotinamide,Dimethylbenzamide, Diethylbenzamide, 1-methylnicotinamide, Salicyclicacid, P-Hydroxybenzoic acid and Benzoate.

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Resorcinol, Pyrocatechol, Pyrogallol, Gentisicacid, Xylenesulfonate, p-toluenesulfonate, Nicotinamide,Dimethylbenzamide, Diethylbenzamide, 1-methylnicotinamide, Salicyclicacid and P-Hydroxybenzoic acid.

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Resorcinol, Pyrocatechol and Pyrogallol,

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Xylenesulfonate and p-toluenesulfonate

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Nicotinamide, Dimethylbenzamide, Diethylbenzamideand 1-methylnicotinamide,

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Gentisic acid, Salicyclic acid, P-Hydroxybenzoicacid and Benzoate.

In one embodiment the hydrotrope or hydrotropes is/are selected from thegroup consisting of: Gentisic acid, Salicyclic acid and P-Hydroxybenzoicacid.

In one embodiment the hydrotrope or hydrotropes are nicotinamide and/orResorcinol. In one embodiment the hydrotrope is nicotinamide.

In one embodiment the hydrotrope is not sodium benzoate.

As shown in the examples herein, the composition of the inventioncomprises a GLP-1 agonist, a delivery agent and a hydrotrope.

The description here below also refers to compositions consisting ofspecific ingredients, the GLP-1 agonist, the delivery agent and thehydrotrope and optionally a lubricant, the term consisting is to beunderstood to nevertheless encompass trace amounts of any substance withno effect on the function of the composition. Such substances can beimpurities remaining in preparation of the GLP-1 agonist, from theproduction of the salt of NAC, the hydrotrope preparation or minimalamounts (below 1%) of any pharmaceutical acceptable excipient that donot affect the quality or absorption of the formulation.

In one embodiment the pharmaceutical composition comprises a balancedamount of the hydrotrope relative to the amount of the delivering agent.The effect of the hydrotrope has been observed over a range ofconcentrations.

In one embodiment the ratio of salt of NAC/hydrotrope (w/w) is at least0.5, such as at least 0.75 or such as at least 1.

In one embodiment the ratio of salt of NAC/hydrotrope (w/w) is 0.5-10.0or such as such as 0.5-8 or such as 0.5-5.

In one embodiment the ratio of salt of NAC/hydrotrope (w/w) is 0.5-10.0or such as 0.75-10.0, 0.5-8.0 or 1-2.0.

In one embodiment the ratio of SNAC/Nicotinamide (w/w) is at least 0.5,such as at least 0.75, such as at least 1.

In one embodiment the ratio of salt of SNAC/Nicotinamide (w/w) is0.5-10.0 or such as 0.5-8 or such as 0.5-5.

In one embodiment the ratio of salt of SNAC/Nicotinamide (w/w) is0.5-10.0 or such as 0.75-10.0, 0.5-8.0 or 1-2.0.

In one embodiment the ratio of SNAC/Resorcinol (w/w) is at least 0.5,such as at least 0.75, such as at least 1. In one embodiment the ratioof salt of SNAC/Resorcinol (w/w) is 0.5-10.0 or such as 0.75-10.0,0.5-8.0 or such as 1-2.0.

In one embodiment the ratio of hydrotrope/salt of NAC (w/w) is at least0.1, such as at least 0.2 or such as at least 0.3. In one embodiment theratio of hydrotrope/salt of NAC (w/w) is 0.1-5.0 or such as 0.1-4.0,0.2-3.0 or 0.25-2.0.

In one embodiment the ratio of Nicotinamide/SNAC/(w/w) is at least0.1-5.0 or such as 0.1-4.0, 0.2-3.0 or 0.25-2.0. In one embodiment theratio of Nicotinamide/SNAC (w/w) is 0.1-5.0 or such as 0.1-4.0, 0.2-3.0or 0.25-2.0.

In one embodiment the ratio of Resorcinol/SNAC/(w/w) is at least 0.1-5.0or such as 0.1-4.0, 0.2-3.0 or 0.25-2.0. In one embodiment the ratio ofResorcinol/SNAC (w/w) is 0.1-5.0 or such as 0.1-4.0, 0.2-3.0 or0.25-2.0.

Likewise, the amount of lubricant maybe be considered relative to thetotal amount of the other excipients, here hydrotrope and deliveryagent, and not including the GLP-1 agonist. Relatively small amounts ofthe lubricant are usually included, such as less than 5% of the totalweight of the other excipients.

In one embodiment the composition comprises less than 5 w/w % lubricantof the total amount of delivery agent and hydrotrope. In one embodimentthe composition comprises 0.25-5%, such as 1-4 w/w % lubricant of thetotal amount of delivery agent and hydrotrope. In further embodimentsthe composition comprises 0.25-5%, such as 1-4 w/w % lubricant of theamount of salt of NAC, such as SNAC, and nicotinamide or resorcinol.

The pharmaceutical composition according to the invention is preferablyproduced in a dosage form suitable for oral administration as describedherein below. In the following the absolute amounts of the ingredientsof the composition of the invention are provided with reference to thecontent in a dosage unit i.e. per tablet, capsule or sachet.

The pharmaceutical compositions of the invention may in a furtherembodiment comprise at most 1000 mg of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) per dose unit. In oneembodiment the invention relates to a composition wherein a dose unitcomprises at most 500 mg of said salt.

In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dose unit is at least 0.15 mmol, such asselected from the group consisting of at least 0.20 mmol, at least 0.25mmol, at least 0.30 mmol, at least 0.35 mmol, at least 0.40 mmol, atleast 0.45 mmol, at least 0.50 mmol, at least 0.55 mmol and at least0.60 mmol.

In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid per dosage unit of thecomposition is up to 2 mmol, such as up to 1.5 mmol, up to 1 mmol, up to0.75 mmol, up to 0.6 mmol, up to 0.5 mmol, up to 0.4 mmol, up to 0.3mmol and up to 0.2 mmol.

In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dose unit of the composition is in the range of0.20-1.5 mmol, 0.25-1.0 mmol 0.30-0.75 mmol or such as 0.45-0.65 mmol.

In some embodiments the amount of SNAC in the composition is at least 50mg, such as at least 75 mg, at least 100 mg, at least 125 mg, at least150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250mg, at least 275 mg and at least 300 mg per dose unit.

In some embodiments the amount of SNAC in the composition is up to 575mg, such as up to 550 mg, up to 525 mg, up to 500 mg, up to 475 mg, upto 450 mg, up to 425 mg, up to 400 mg, up to 375 mg, up to 350 mg, up to325 mg per dose unit, or up to 300 mg per dose unit.

In some embodiments the amount of SNAC in the composition is in therange of 75-400 mg, such as from 80-350 mg, such as from around 100 toaround 300 mg per dose unit.

In an embodiment, a dose unit of the pharmaceutical compositions of theinvention comprises 0.1-100 mg of the GLP-1 agonist.

In some embodiments a dose unit of the composition comprises an amountof GLP-1 agonist is in the range of 0.1-50 mg, 0.2 to 50 mg, 0.5 to 50mg or 1 to 40 mg.

In some embodiments a dose unit of the composition comprises an amountof GLP-1 agonist is in the range of 0.1-50 mg, 0.1-40 mg, 0.1-30 mg or0.1-20 mg.

In some embodiments a dose unit comprises 0.5-5 mg of the GLP-1 agonist,such as 0.75-4½%2 mg, such as 1, 1½, 2, 2½ or 3 mg or 3½, 4, 4½ mg, suchas 1-3 or 3-5 mg of the GLP-1 agonist per dose unit.

In some embodiments a dose unit comprises 2 to 20 mg of the GLP-1agonist, such as 2-15 mg, such as 2, 3, 4 or 5 mg, or such as 8, 10, 12or 14 mg, such as 15 mg or such as 20 mg of the GLP-1 agonist per doseunit.

In some embodiments a dose unit comprises 5 to 50 mg of the GLP-1agonist, such as 10-45 mg, such as 20, 30 or 40 mg, or such as 25, 35,or 45 mg, or such as 30-50 mg or such as 20-40 mg of the GLP-1 agonistper dose unit.

As described above the amount of the hydrotrope is to be balanced withthe amount of the delivering agents, such as SNAC, but in general a doseunit of the compositions of the invention comprises 10-600 mg of thehydrotrope.

In on embodiment a dose unit comprises 20-400 mg, such as 40-300, suchas 50-200 mg, such as 50-175 mg of the hydrotrope.

In on embodiment a dose unit comprises 100-600 mg, such as 100-500, suchas 150-400 mg, such as 150-300 mg of the hydrotrope.

In further such embodiments, a unit dose of the composition according tothe invention comprises 50-600 mg nicotinamide and/or resorcinol.

In on embodiment a dose unit comprises 50-400 mg, such as 50-300, suchas 50-200 mg, such as 50-175 mg nicotinamide and/or resorcinol.

In further such embodiments a unit dose of the composition according tothe invention comprises 50-600 mg nicotinamide. In one embodiment a doseunit comprises 50-400 mg, such as 50-300, such as 50-200 mg, such as50-175 mg nicotinamide.

In one embodiment a unit dose of the composition according to theinvention comprises:

-   -   i) 0.1-10 mg GLP-1 agonist, such as GLP-1 agonist is        Semaglutide, GLP-1 agonist B or GLP-1 agonist C.    -   ii) 25-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (NAC), such as the sodium salt of NAC (SNAC) and    -   iii) 20-600 mg, such as 50-200 mg, nicotinamide or resorcinol        and    -   iv) 0-10 mg lubricant.

In one embodiment a unit dose of the composition according to theinvention comprises:

-   -   i) 0.1-10 mg GLP-1 agonist, such as GLP-1 agonist is        Semaglutide, GLP-1 agonist B or GLP-1 agonist C.    -   ii) 150-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic        acid (NAC), such as the sodium salt of NAC (SNAC) and    -   iii) 100-600 mg nicotinamide or resorcinol and    -   iv) 0-10 mg lubricant.

The amount of GLP-1 agonist may be varied depending on identity of theGLP-1 agonist and the effect desired, i.e. a higher content may berelevant for treating obesity compared to diabetes.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 0.5-10 mg GLP-1 agonist, 100-400 mg hydrotrope and 2-3mg lubricant.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 1½-10 mg GLP-1 agonist, 100-400 mg hydrotrope and 2-3mg lubricant.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 5-50 mg GLP-1 agonist, 100-400 mg hydrotrope and 2-3 mglubricant.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 0.5-10 mg GLP-1 agonist, 100-400 mg nicotinamide and2-3 mg lubricant.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 1½-10 mg GLP-1 agonist, 100-400 mg nicotinamide and 2-3mg lubricant.

In a preferred embodiment a unit dose of the composition comprises200-400 mg SNAC, 5-50 mg GLP-1 agonist, 100-400 mg nicotinamide and 2-3mg lubricant.

In one embodiment a unit dose of the composition according to theinvention comprises:

-   -   i) 0.1-10 mg GLP-1 agonist, such as GLP-1 agonist is        Semaglutide, GLP-1 agonist B or GLP-1 agonist C.    -   ii) 25-400 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (NAC), such as the sodium salt of NAC (SNAC) and    -   iii) 20-200 mg nicotinamide or resorcinol and    -   iv) 0-10 mg lubricant.

The amount of GLP-1 agonist may be varied depending on identity of theGLP-1 agonist and the effect desired, i.e. a higher content may berelevant for treating obesity compared to diabetes.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 0.5-5 mg GLP-1 agonist, 20-200 mg hydrotrope and 1-3 mglubricant.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 1½-10 mg GLP-1 agonist, 20-200 mg hydrotrope and 1-3 mglubricant.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 5-50 mg GLP-1 agonist, 20-200 mg hydrotrope and 1-3 mglubricant.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 0.5-5 mg GLP-1 agonist, 20-200 mg nicotinamide and 1-3mg lubricant.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 1½-10 mg GLP-1 agonist, 20-200 mg nicotinamide and 1-3mg lubricant.

In a preferred embodiment a unit dose of the composition comprises80-120 mg SNAC, 5-50 mg GLP-1 agonist, 20-200 mg nicotinamide and 1-3 mglubricant.

Dosage Form

The composition may be administered in several dosage forms, for exampleas a tablet; a coated tablet; a sachet or a capsule such as hard or softgelatine capsule and all such compositions are considered solid oraldosage forms.

The composition may further be compounded in a drug carrier or drugdelivery system, e.g. in order to improve stability and/or solubility orfurther improve exposure. The composition may be a freeze-dried orspray-dried composition.

The composition may be in the form of a dose unit, such as tablet. Insome embodiments the weight of the unit dose is in the range of 50 mg to1000 mg, such as in the range of 50-750 mg, or such as about 100-500 mg.In some embodiments the weight of the dose unit is in the range of 75 mgto 350 mg, such as in the range of 50-300 mg or 100-400 mg.

In some embodiments the composition may be granulated prior to beingcompressed to tablets. The composition may comprise a granular partand/or an extra-granular part, wherein the granular part has beengranulated and the extra-granular part has been added after granulation.

The granular part may comprise one or more of the GLP-1 agonist, thedelivery agent and/or the hydrotrope. In an embodiment the granular partmay comprise a further excipient, such as a lubricant and/or glidant. Insome embodiments the granular part comprises the delivery agent and thehydrotrope.

In one embodiment the hydrotrope is included in the granular part, theextra-granular part or both.

In some embodiments the granular part comprises magnesium stearate orglyceryl dibehenate.

The GLP-1 agonist may be included in the granular part or theextra-granular part. In some embodiments the extra-granular partcomprises the GLP-1 agonist. In an embodiment the extra-granular partmay further comprise a lubricant and/or a glidant. In an embodiment thegranular part may comprise a lubricant and/or a glidant. In anembodiment the granular part and the extra-granular part comprise alubricant and/or a glidant.

In some embodiments the lubricant and/or a glidant is magnesium stearateor glyceryl dibehenate.

Preparation of Composition

Preparation of a composition according to the invention may be performedaccording to methods known in the art.

To prepare a dry blend of tabletting material, the various componentsare weighed, optionally delumped or sieved and then combined. The mixingof the components may be carried out until a homogeneous blend isobtained.

The term “granules” refers broadly to pharmaceutical ingredients in theform of particles, granules and aggregates which are used in thepreparation of solid dose formulations. Generally, granules are obtainedby processing a powder or a blend to obtain a solid which issubsequently broken down to obtain granules of the desired size.

If granules are to be used in the tabletting material, granules may beproduced in a manner known to a person skilled in the art, for exampleusing wet granulation methods known for the production of “built-up”granules or “broken-down” granules. Methods for the formation ofbuilt-up granules may operate continuously and comprise, for examplesimultaneously spraying the granulation mass with granulation solutionand drying, for example in a drum granulator, in pan granulators, ondisc granulators, in a fluidized bed, by spray-drying orspray-solidifying, or operate discontinuously, for example in afluidized bed, in a rotary fluid bed, in a batch mixer, such as a highshear mixer or a low shear mixer, or in a spray-drying drum. Methods forthe production of broken-down granules, which may be carried outdiscontinuously and in which the granulation mass first forms a wetaggregate with the granulation solution, which is subsequentlycomminuted or by other means formed into granules of the desired sizeand the granules may then be dried. Suitable equipment for thegranulation step are planetary mixers, low shear mixers, high shearmixers, extruders and spheronizers, such as an apparatus from thecompanies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach,Alexanderwerk, Ytron, Wyss & Probst, Werner & Pfleiderer, HKD, Loser,Fuji, Nica, Caleva and Gabler. Granules may be also formed by drygranulation techniques in which one or more of the excipient(s) and/orthe active pharmaceutical ingredient is compressed to form relativelylarge moldings, for example slugs or ribbons, which are comminuted bygrinding, and the ground material serves as the tabletting material tobe later compacted. Suitable equipment for dry granulation is rollercompaction equipment from Gerteis, but not limited hereto, such asGerteis MICRO-PACTOR, MINI-PACTOR and MARCO-PACTOR.

Further methods of obtaining granules can include hot melt extrusion,spray drying, spray granulation and/or ball milling.

In an embodiment the invention relates to a composition comprising

-   -   i. a GLP-1 agonist,    -   ii. a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC)        and    -   iii. a hydrotrope        wherein the composition comprises a granulate of ii) and iii).

In embodiments where the granular part comprises both the delivery agentand the hydrotrope these excipients may be co-processed prior to or inthe preparation of the granules.

The granulation maybe be obtained by various methods as described above,wherein ii) and iii) are initially mixed either as powders or by thepreparation of a solution comprising both ingredients.

Granules of ii) and iii) may then be obtained by dry granulation of theblend, such as by roller compaction. In an alternative embodiment theblend may be hot melt extruded to obtain an extrudate which issubsequently milled to obtain the granules. This material can then beused directly or in dry granulation/roller compaction process to obtainthe final granules.

In one embodiment a solution of ii) and iii) is prepared and subject tospray granulation whereby granules are directly obtained. Alternatively,the solution can be used in a fluid bed spray granulation process. Inone embodiment spray drying can be used followed by drygranulation/roller compaction to obtain the granules.

In order to obtain a homogenous product one or more sieving step(s) canbe included prior to the final dry granulation step/roller compaction ortablet compression.

To compact the tabletting material into a solid oral dosage form, forexample a tablet, a tablet press may be used. In a tablet press, thetabletting material is filled (e.g. force fed or gravity fed) into a diecavity. The tabletting material is then compacted by a set of punchesapplying pressure. Subsequently, the resulting tablet is ejected fromthe tablet press. The above mentioned tabletting process is subsequentlyreferred to herein as the “compression process”. Suitable tablet pressesinclude, but are not limited to, rotary tablet presses and eccentrictablet presses. Examples of tablet presses include, but are not limitedto, the Fette 102i (Fette GmbH), the Korsch XL100, the Korsch PH 106rotary tablet press (Korsch AG, Germany), the Korsch EK-O eccentrictabletting press (Korsch AG, Germany) and the Manesty F-Press (ManestyMachines Ltd., United Kingdom).

In some embodiments the invention relates to a method of preparation acomposition according to the invention. In one embodiment the method ofpreparing a tablet comprises; a) granulation of a mixture comprising thedelivery agent and the hydrotrope b) blending of the granulates of a)with a GLP-1 agonist, and then c) compression of the blend into tablets.The granulation may be a wet or dry granulation. As described above alubricant such as magnesium stearate or glyceryl behenate may beincluded in steps a), b) and/or c).

In one embodiment the invention relates to a method for producing asolid pharmaceutical composition comprising the steps of;

-   -   i) obtaining a blend comprising a salt of NAC and a hydrotrope,    -   ii) co-processing the blend of i) and    -   iii) preparing said solid pharmaceutical composition using the        product of ii).

In one embodiment the method is for producing a solid pharmaceuticalcomposition comprising the steps of;

-   -   i) obtaining a blend comprising a salt of NAC and a hydrotrope,    -   ii) heat melt extruding the blend of i) and    -   iii) preparing said solid pharmaceutical composition, such as        tablets, using the extrudate of ii).

The method may as described herein include further steps, such as a stepof admixing the extrudate of ii) with an active pharmaceuticalingredient and optionally any further excipients and preparing saidsolid pharmaceutical composition using the mixture.

Pharmaceutical Indications

The present invention also relates to a composition of the invention foruse as a medicament. In particular embodiments the composition of theinvention may be used for the following medical treatments, allpreferably relating one way or the other to diabetes:

(i) prevention and/or treatment of all forms of diabetes, such ashyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetesof the young), gestational diabetes, and/or for reduction of HbA1C;

(ii) delaying or preventing diabetic disease progression, such asprogression in type 2 diabetes, delaying the progression of impairedglucose tolerance (IGT) to insulin requiring type 2 diabetes, and/ordelaying the progression of non-insulin requiring type 2 diabetes toinsulin requiring type 2 diabetes;

(iii) improving β-cell function, such as decreasing β-cell apoptosis,increasing β-cell function and/or β-cell mass, and/or for restoringglucose sensitivity to β-cells;

(iv) prevention and/or treatment of cognitive disorders;

(v) prevention and/or treatment of eating disorders, such as obesity,e.g. by decreasing food intake, reducing body weight, suppressingappetite, inducing satiety; treating or preventing binge eatingdisorder, bulimia nervosa, and/or obesity induced by administration ofan antipsychotic or a steroid; reduction of gastric motility; and/ordelaying gastric emptying;

(vi) prevention and/or treatment of diabetic complications, such asneuropathy, including peripheral neuropathy; nephropathy; orretinopathy;

(vii) improving lipid parameters, such as prevention and/or treatment ofdyslipidemia, lowering total serum lipids; lowering HDL; lowering small,dense LDL; lowering VLDL: lowering triglycerides; lowering cholesterol;increasing HDL; lowering plasma levels of lipoprotein a (Lp(a)) in ahuman; inhibiting generation of apolipoprotein a (apo(a)) in vitroand/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases, such assyndrome X; atherosclerosis; myocardial infarction; coronary heartdisease; stroke, cerebral ischemia; an early cardiac or earlycardiovascular disease, such as left ventricular hypertrophy; coronaryartery disease; essential hypertension; acute hypertensive emergency;cardiomyopathy; heart insufficiency; exercise tolerance; chronic heartfailure; arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis;mild chronic heart failure; angina pectoris; cardiac bypass reocclusion;intermittent claudication (atheroschlerosis oblitterens); diastolicdysfunction; and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases, such asinflammatory bowel syndrome; small bowel syndrome, or Crohn's disease;dyspepsia; and/or gastric ulcers;

(x) prevention and/or treatment of critical illness, such as treatmentof a critically ill patient, a critical illness poly-nephropathy (CIPNP)patient, and/or a potential CIPNP patient; prevention of criticalillness or development of CIPNP; prevention, treatment and/or cure ofsystemic inflammatory response syndrome (SIRS) in a patient; and/or forthe prevention or reduction of the likelihood of a patient sufferingfrom bacteraemia, septicaemia, and/or septic shock duringhospitalisation; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a particular embodiment, the indication is selected from the groupconsisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii),and/or (iii); or indication (v), indication (vi), indication (vii),and/or indication (iix). In another particular embodiment, theindication is (i). In a further particular embodiment the indication is(v). In a still further particular embodiment the indication is (iix).In some embodiments the indications are type 2 diabetes and/or obesity.

The invention further relates to a method of treatment of an individualin need thereof, comprising administering a therapeutically activeamount of a composition according to the present invention to saidindividual. In a further such embodiments one or more dose units may beadministered to said individual in need.

Method of Treatment

The invention further relates to a method of treating a subject in needthereof, comprising administering a therapeutically effective amount ofa composition according to the present invention to said subject. In oneembodiment the method of treatment is for treatment of diabetes orobesity and/or the further indications specified above.

In some embodiments, a method for treating diabetes is describedcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical composition comprising a GLP-1agonist, a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), ahydrotrope and optionally, a lubricant.

In some embodiments, a method for treating diabetes is describedcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical composition comprising

-   -   i) 0.1-30 mg GLP-1 agonist, such as GLP-1 agonist is        Semaglutide, GLP-1 agonist B or GLP-1 agonist C.    -   ii) 25-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (NAC), such as the sodium salt of NAC (SNAC) and    -   iii) 20-600 mg, such as 50-200 mg, nicotinamide or resorcinol        and    -   iv) 0-10 mg lubricant.

In some embodiments, the GLP-1 agonist is semaglutide having a formulaofN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37)and the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) issodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC).

In some embodiments, the GLP-1 agonist isN^(ε27)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl],N^(ε36)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (GLP-1 agonist C).

Various examples of a lubricant are described, including magnesiumstearate. The composition is administered orally and is in a form of atable, capsule or a sachet.

In a further such embodiments one or more dose units may be administeredto said subject in need.

Combination Treatment

The treatment with a composition according to the present invention mayalso be combined with one or more additional active pharmaceuticalingredient(s), e.g. selected from antidiabetic agents, antiobesityagents, appetite regulating agents, antihypertensive agents, agents forthe treatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity. Examples of these pharmacologically active substances are:Insulin, sulphonylureas, biguanides, meglitinides, glucosidaseinhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV)inhibitors, sodium glucose linked transporter 2 (SGLT2) inhibitors;canagliflozin, dapagliflozin, empagliflozin, ertugliflozin,ipragliflozin, tofogliflozin, luseogliflozin, bexagliflozin,remogliflozin etabonate and sotagliflozin, particulally dapagliflozinand empagliflozin, inhibitors of hepatic enzymes involved in stimulationof gluconeogenesis and/or glycogenolysis, glucose uptake modulators,compounds modifying the lipid metabolism such as antihyperlipidemicagents as HMG CoA inhibitors (statins), Gastric Inhibitory Polypeptides(GIP analogues), compounds lowering food intake, RXR agonists and agentsacting on the ATP-dependent potassium channel of the β-cells;Cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol, dextrothyroxine, neteglinide,repaglinide; β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, alatriopril, quinapril and ramipril, calcium channelblockers such as nifedipine, felodipine, nicardipine, isradipine,nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin,urapidil, prazosin and terazosin; CART (cocaine amphetamine regulatedtranscript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2receptor agonists, Y4 receptor agonists, mixed Y2/Y4 receptor agonists,MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumour necrosisfactor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP(corticotropin releasing factor binding protein) antagonists, urocortinagonists, 33 agonists, oxyntomodulin and analogues, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators, TR P agonists; histamine H3antagonists, Gastric Inhibitory Polypeptide agonists or antagonists (GIPanalogues), gastrin and gastrin analogues.

The invention as described herein is, without limitation hereto furtherdefined by the embodiments described here below and the claims of thedocument.

EMBODIMENTS

-   -   1. A composition comprising        -   i) a GLP-1 agonist,        -   ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid            (NAC) and        -   iii) a hydrotrope.    -   2. The composition according to embodiment 1, wherein the        hydrotrope is selected from the group of hydrotropes consisting        of: Nipecotamide, Nicotinamide, p-hydroxybenzoic acid sodium,        N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl        nicotinamide, Sodium salicylate, Resorcinol, Sodium benzoate,        Sodium Xylenesulfonate, Sodium p-toluenesulfonate,        1-Methylnicotinamide, Pyrogallol, Pyrocathecol, Epigallocatechin        gallate, Tannic acid and Gentisic acid sodium salt hydrate.    -   3. The composition according to embodiment 1, wherein the        hydrotrope is selected from the group of hydrotropes consisting        of: Nipecotamide, Nicotinamide, p-hydroxybenzoic acid sodium,        N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl        nicotinamide, Sodium salicylate, Resorcinol, Sodium        Xylenesulfonate, Sodium p-toluenesulfonate,        1-Methylnicotinamide, Pyrogallol, Pyrocathecol, Epigallocatechin        gallate, Tannic acid and Gentisic acid sodium salt hydrate.    -   4. The composition according to embodiment 1, 2 or 3, wherein        the hydrotrope comprises an aromatic ring structure.    -   5. The composition according to any of the embodiments 1-4,        wherein the hydrotrope is not sodium benzoate.    -   6. The composition according to any of the embodiments 1-5,        wherein the hydrotrope has a molecular weight of less than 400        g/mol.    -   7. The composition according to any of the embodiments 1-6,        wherein the hydrotrope has a molecular weight of at least 80        g/mol.    -   8. The composition according to any of the embodiments 1-7,        wherein the hydrotrope increases the solubility of SNAC at least        2-fold.    -   9. The composition according to any of the embodiments 1-7,        wherein the hydrotrope is increases the solubility of SNAC at        least 5-fold.    -   10. The composition according to embodiment 8 or embodiment 9,        wherein the solubility is measured at a concentration of 200        mg/ml of the hydrotrope at pH 6.    -   11. The composition according to embodiment 8, 9 or 10, where in        the solubility is measured as room temperature.    -   12. The composition according to embodiment 8, 9 or 10, where in        the solubility is measured as described in Assay I herein.    -   13. The composition according to embodiment 1, wherein the        hydrotrope is Nicotinamide or Resocinol.    -   14. The composition according to embodiment 1, wherein the        hydrotrope is Nicotinamide.    -   15. The composition according to any of the previous        embodiments, wherein the ratio of salt of NAC/hydrotrope (w/w)        is at least 0.5.    -   16. The composition according to any of the previous        embodiments, wherein the ratio of salt of NAC/hydrotrope (w/w)        is 0.5-10.0 or such as 0.75-10.0, 0.5-8.0 or 1-2.0.    -   17. The composition according to any of the previous        embodiments, wherein the ratio of hydrotrope/salt of NAC (w/w)        is at least 0.1.    -   18. The composition according to any of the previous        embodiments, wherein the ratio of hydrotrope/salt of NAC (w/w)        is 0.1-5.0 or such as 0.1-4.0, 0.2-3.0 or 0.25-2.0.    -   19. The composition according to any of the previous        embodiments, wherein the composition comprises a lubricant.    -   20. The composition according to any of the previous        embodiments, wherein the composition comprises 0.25-5 w/w %        lubricant of the total amount of other excipients.    -   21. The composition according to any of the previous        embodiments, wherein the composition comprises a lubricant        selected from magnesium stearate and glyceryl dibehenate.    -   22. The composition according to any of the previous        embodiments, wherein the composition comprises 0.25-5 w/w %        magnesium stearate of the total amount of SNAC and nicotinamide.    -   23. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist has T ½ of at least 24        hours in minipigs.    -   24. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist has T ½ of at least 2        hours in rats.    -   25. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist has an EC50 (without HSA)        of at most 100 pM, such as at most 50.    -   26. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist has an EC50 (without 1%        HSA) of at most 100 pM, such as at most 50.    -   27. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist has a molar mass of at        most 50 000 g/mol.    -   28. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist comprises an albumin        binding substituent.    -   29. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist comprises a fatty acid or        a fatty diacid.    -   30. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist comprises a C16, C18 or        C20 fatty acid or a C16, C18 or C20 fatty diacid.    -   31. The composition according to any of the previous        embodiments, wherein the GLP-1 agonist is selected from the        group consisting of: liraglutide, semaglutide, GLP-1 agonist B        and GLP-1 agonist C.    -   32. The composition according to any of the previous        embodiments, wherein a dose unit comprises 0.1-50 mg of the        GLP-1 agonist.    -   33. The composition according to any of the previous        embodiments, wherein the salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) is selected        from the group consisting of the sodium salt, potassium salt        and/or calcium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic        acid.    -   34. The composition according to any of the previous embodiments        comprising or consisting of:        -   i) a GLP-1 agonist, such as Semaglutide, GLP-1 agonist B or            GLP-1 agonist C.        -   ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid            (NAC), such as the sodium salt of NAC (SNAC)        -   iii) nicotinamide or resorcinol and        -   iv) a lubricant.    -   35. The composition according to any of the previous        embodiments, wherein a dose unit comprises at most 1000 mg of        said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC).    -   36. The composition according to any of the previous        embodiments, wherein a unit dosage comprises        -   i) 0.1-30 mg, such as 0.1-20 mg GLP-1 agonist, such as            Semaglutide, GLP-1 agonist B or GLP-1 agonist C.        -   ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic            acid (NAC), such as the sodium salt of NAC (SNAC) and        -   iii) 50-200 mg nicotinamide or resorcinol and        -   iv) 0-10 mg lubricant.    -   37. The composition according to any of the previous        embodiments, wherein a unit dosage comprises        -   i) 0.1-30 mg, such as 0.1-20 mg Semaglutide        -   ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic            acid (NAC), such as the sodium salt of NAC (SNAC) and        -   iii) 50-200 mg nicotinamide or resorcinol and        -   iv) 0-10 mg lubricant.    -   38. The composition according to any of the previous embodiments        1-36, wherein a unit dosage comprises        -   i) 0.1-30 mg, such as 0.1-20 mg            N^(ε27)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl],            N^(ε36)-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,            Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly (GLP-1            agonist C),        -   ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic            acid (NAC), such as the sodium salt of NAC (SNAC) and        -   iii) 50-200 mg nicotinamide or resorcinol and        -   iv) 0-10 mg lubricant.    -   39. The composition according to any of the previous embodiments        1-36, wherein a unit dosage comprises        -   i) 0.1-30 mg, such as 0.1-20 mg GLP-1 agonist with the            following structure

-   -   -   ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic            acid (NAC), such as the sodium salt of NAC (SNAC) and        -   iii) 50-200 mg nicotinamide or resorcinol and        -   iv) 0-10 mg lubricant.

    -   40. The composition according to any of the previous        embodiments, wherein the composition is a solid composition,        such as a solid oral dosage form.

    -   41. The composition according to any of the previous        embodiments, wherein the composition comprises a granulate        comprising ii).

    -   42. The composition according to any of the previous        embodiments, wherein the composition comprises a granulate        comprising ii) and iii).

    -   43. The composition according to any of the embodiments 41 and        42, wherein ii) and iii) are co-processed prior to granulation.

    -   44. The composition according to any of the embodiments 41, 42        and 43, wherein the granulate is obtained by hot melt extrusion        and milling, spray granulation, wet granulation or dry        granulation.

    -   45. The composition according to any of the embodiments 43 or        44, wherein ii) and iii) are blended prior to granulation.

    -   46. The composition according to any of the embodiments 43, 44        or 45, wherein a solution of ii) and iii) is prepared prior to        granulation.

    -   47. The composition according to embodiment 46, wherein the        granulate is obtained by spray granulation or wet granulation.

    -   48. The composition according to any of the embodiments 46,        wherein the solution is spray dried prior to dry granulation.

    -   49. The composition according to embodiment 43, 44 or 45,        wherein the granulate is obtained hot melt extrusion and        milling.

    -   50. The composition according to embodiment 45, wherein the        blend of ii) and iii) is hot melt extruded.

    -   51. The composition according to embodiment 50, wherein the        extrudate is milled.

    -   52. The composition according to any of the embodiment 41-51,        wherein the granulate is obtained by roller compaction.

    -   53. The composition according to any of the embodiments 46-52,        wherein the co-processed ii) and iii) granulate is sieved.

    -   54. The composition according to embodiment 46-53,wherein the        milled hot melt extrudate is sieved through a screen of 50-500        μm.

    -   55. The composition according to embodiment 48, wherein the        spray dried product is sieved through a screen of 50-500 μm.

    -   56. The composition according to embodiment 41-46, wherein the        granulate is obtained by spray granulation.

    -   57. The composition according to embodiment 56, wherein a        solution of ii) and iii) is processed by spouted bed or fluid        bed spray granulation.

    -   58. The composition according to embodiments 56 and 57, wherein        the granulation product is sieved through a 100-500 μm μm        screen.

    -   59. The composition according to any of the embodiments 41-58,        wherein the composition comprises an extra-granular part.

    -   60. The composition according to any of the embodiments 41-58,        wherein the granulate is blended with any further excipients        prior to compression.

    -   61. The composition according to any of the embodiments 41-58,        wherein the hydrotrope is included in the intra-granular part.

    -   62. The composition according to any of the embodiments 41-58,        wherein the GLP-1 agonist is included in an extra granular part.

    -   63. The composition according to any of the embodiments 1-62,        wherein the composition is produced by a method comprising the        steps of:        -   a) granulation of a mixture comprising the delivery agent            and the hydrotrope        -   b) blending of the granulates of a) with the GLP-1 agonist,            and        -   c) compressing the blend of b).

    -   64. A composition consisting of:        -   i) a GLP-1 agonist,        -   ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid            (NAC)-        -   iii) nicotinamide or resocinol and        -   iv) optionally a lubricant, such as magnesium stearate.

    -   65. The composition according embodiment 64, wherein the GLP-1        agonist is Semaglutide, GLP-1 agonist B or GLP-1 agonist C.

    -   66. The composition according embodiment 64, wherein ii) is the        sodium salt of NAC (SNAC).

    -   67. The composition according to any of the previous        embodiments, wherein the composition is a pharmaceutical        composition.

    -   68. The composition according to embodiment 67, wherein the        composition is for oral administration.

    -   69. The composition according to embodiment 67, wherein the        composition is a solid composition, such as a tablet, a capsule        or a sachet for oral administration.

    -   70. The composition according to any of the previous        embodiments, wherein the composition is a pharmaceutical        composition for use in a method of treating diabetes and/or        obesity.

    -   71. A method for producing a solid pharmaceutical composition        comprising the steps of;        -   i) obtaining a blend comprising a salt of NAC and a            hydrotrope,        -   ii) co-processing the blend of i) and        -   iii) preparing said solid pharmaceutical composition using            the product of ii).

    -   72. A method for producing a solid pharmaceutical composition        according to embodiment 71, wherein the co-processing if        step ii) is performed by        -   a) heat melt extrusion        -   b) spray-granulation        -   c) dry granulation or        -   d) spray-drying.

    -   73. A method for producing a solid pharmaceutical composition        comprising the steps of;        -   i) obtaining a blend comprising a salt of NAC and a            hydrotrope,        -   ii) heat melt extruding the blend of i)        -   iii) milling the extrudate of ii) and        -   iv) preparing said solid pharmaceutical composition using            the product of iii).

    -   74. A method for producing a solid pharmaceutical composition        comprising the steps of        -   i) obtaining a blend comprising a salt of NAC and a            hydrotrope,        -   ii) co-processing the blend of i),        -   iii) admixing the product of ii) with an active            pharmaceutical ingredient and optionally any further            excipients and        -   iv) preparing said solid pharmaceutical composition using            the mixture of iii).

    -   75. A method for producing a solid pharmaceutical composition        comprising the steps of        -   i) obtaining a blend comprising a salt of NAC and a            hydrotrope,        -   ii) heat melt extruding the blend of i)        -   iii) milling the extrudate of ii)        -   iv) admixing the product of ii) with an active            pharmaceutical ingredient and optionally any further            excipients and        -   v) preparing said solid pharmaceutical composition using the            mixture of iii).

    -   76. A method for producing a composition according to any of the        previous embodiments 71-74, wherein the pharmaceutical        composition is defined as in any of the previous embodiments        1-70

    -   77. A method for treatment of diabetes or obesity comprising        administering to a subject in need a therapeutically effective        amount of a composition according to embodiments 1-70 or a        composition produced by any of the method of embodiments 71-76.

    -   78. The method according to embodiment 77 wherein said        composition is administered, once daily or less frequent.

EXAMPLES Materials and Methods

Assay I: SNAC Solubility in Combination with Selected Hydrotropes

A series of 18 different hydrotropes were selected for testing.Hydrotropes are weighed off and dissolved in 5 mL ultrapure water (200mg/mL) and pH was titrated to pH 6 by addition of 2M HCl. SubsequentlySNAC (200 mg) is added to the samples and placed on magnetic stirrers(400 rpm). The pH is maintained at pH 6 throughout the experiment byaddition of 2M HCl.

After 4 hours of incubation at room temperature the samples werefiltered through 0.45 μm syringe filters and the concentration of SNACin solution is determined using a RP-HPLC method for detection of SNAC.The sample content is calculated based on the peak area of the SNAC peakin the chromatogram relative to the peak area of the SNAC references.Results obtained are presented in table 1, demonstrating that themajority of hydrotropes increase solubility of SNAC significantly.

TABLE 1 Hydrotropic effect of selected hydrotropes (200 mg/mL) on SNACsolubility at pH 6 Fold SNAC increase Replicates concentration inHydrotrope (n) (mg/mL) solubility SNAC control 1 0.59 1 (no hydrotrope)Nipecotamide 1 1.55 2.6 Nicotinamide 5 8.63 14.6 p-hydroxybenzoic acid 11.25 2.1 sodium N,N dimethyl urea 1 2.34 4.0 N,N dimethyl benzamide 422.46 38 N,N diethyl nicotinamide 1 4.58 7.8 Sodium salicylate 1 1.592.7 Resorcinol 6 29.95 51 Sodium benzoate 2 1.25 2.1 Urea 1 0.77 1.3Sodium Xylenesulfonate 1 2.01 3.4 Sodium 1 1.78 3.0 p-toluenesulfonate1-Methylnicotinamide 1 2.20 3.7 Pyrogallol 4 8.98 15 Pyrocathecol 123.95 40.6 Epigallocatechin gallate 1 5.66 9.6 Tannic acid 1 6.31 10.7Gentisic acid sodium salt 1 2.72 4.6 hydrate

Assay II: SNAC Solubility in Varying Concentrations of Nicotinamide andResorcinol

Nicotinamide and resorcinol was weighed off and dissolved in 5 mLultrapure water to the final concentrations shown in FIGS. 1A & B and pHwas titrated to pH 6 by addition of 2M HCl. Subsequently SNAC (200 mg)was added to the samples placed on magnetic stirrers (400 rpm) and pH ismaintained at pH 6 throughout the experiment by addition of 2M HCl.

After 4 hours of incubation samples were filtered through 0.45 μmsyringe filters and the concentration of SNAC in solution is determinedusing a RP-HPLC method for detection of SNAC. The sample content iscalculated based on the peak area of the SNAC peak in the chromatogramrelative to the peak area of the SNAC references. The results are shownin FIG. 1 demonstrating a concentration dependent effect on SNACsolubility of both hydrotropes.

Assay III: Pharmacokinetic Studies in Beagle Dogs

Pharmacokinetic (PK) studies in Beagle dogs are conducted to determinethe exposure of the GLP-1 agonists after peroral administration ofdifferent dosage forms.

For the pharmacokinetic studies male Beagle dogs are used, 1 to 5 yearsof age and weighing approximately 10-12 kg at the start of the studies.The dogs are group housed in pens (12 hours light: 12 hours dark), andfed individually and restrictedly once daily with Royal Canin MediumAdult dog (Royal Canin Products, China Branch, or Brogaarden A/S,Denmark). Exercise and group social are permitted daily, wheneverpossible. The dogs are used for repeated pharmacokinetic studies with asuitable wash-out period between successive dosing's. An appropriateacclimatisation period is given prior to initiation of the firstpharmacokinetic study. All handling, dosing and blood sampling of theanimals are performed by trained and skilled staff. Before the studiesthe dogs are fasted overnight and from 0 to 4 h after dosing. Besides,the dogs are restricted to water 1 hour before dosing until 4 hoursafter dosing, but otherwise have ad libitum access to water during thewhole period.The GLP-1 agonist tablets used for the per oral studies described hereinare immediate release SNAC-based tablets dosed orally.The tablets containing the GLP-1 agonist are administered in thefollowing manner: 10 min prior to tablet administration the dogs aredosed subcutaneously with approximately 3 nmol/kg of SEQ ID NO: 3). Thetablets are placed in the back of the mouth of the dog to preventchewing. The mouth is then closed and 10 mL of tap water is given by asyringe to facilitate swallowing of the tablet. Alternatively, 40 mL ofwater is administered by gavage just prior to tablet dosing, where afterthe tablet is dosed and 10 mL of tap water is given by a syringe tofacilitate swallowing of the tablet.

Blood Sampling

Blood is sampled at predefined time points for up till 10 hr post dosingto adequately cover the full plasma concentration-time absorptionprofile of the GLP-1 agonist.For each blood sampling time point approximately 0.8 mL of whole bloodis collected in a 1.5 mL EDTA coated tube, and the tube is gently turnedto allowing mixing of the sample with the EDTA. Blood samples (forexample 0.8 mL) are collected in EDTA buffer (8 mM) and then centrifugedat 4° C. and 2000G for 10 minutes. Plasma is pipetted into Micronictubes on dry ice, and kept at −20° C. until analysis.Blood samples are taken as appropriate, for example from a venflon inthe cephalic vein in the front leg for the first 2 hours and then withsyringe from the jugular vein for the rest of the time points (the firstfew drops are allowed to drain from the venflon to avoid heparin salinefrom the venflon in the sample).

General Methods for Tablet Preparation Method 1: Blending for DryGranulation

Blending is carried out by manual geometric mixing nicotinamide orresorcinol with SNAC followed by blending on a turbula mixer (7 min, 25rpm). In cases where the magnesium stearate is not included in theinitial blending step it was added in a secondary blending step bymanual geometric mixing followed by blending on a turbula mixer (2 min,25 rpm).

Method 2: Dry Granulation

Dry granulation is carried out by roller compaction on a GerteisMICRO-PACTOR. The roller speed is set at 1 rpm and roller compactionforce at 6 kN/cm, fill depth is 8 mm. Subsequent to dry granulation handsieving of ribbons into granules using an 800 μm wire mesh screen iscarried out.

Method 3: Hot Melt Extrusion

Hot melt extrusion is carried out on a Thermo Scientific Process 11 twinscrew extruder. SNAC and nicotinamide or resorcinol are blended on aturbula prior to feeding into the extruder (7 min 25 rpm). The equipmentis operated at process temperatures varying between 200° C. to 105° C.along the barrel to facilitate the melt extrusion. The screw speed isvaried between 50-1000 rpm and material is fed into the extruder using agravimetric feeder at varying feed rates and extruded through a 2 mmdiameter circular die. The resulting extrudates are manually sieved intogranules using a final mesh screen between 350 and 149 μm.

Method 4: Spray Drying

Spray drying is carried out on a Büchi B-290 spray drier mounted with a1.5 mm nozzle (0.7 mm tip and 0.7 mm needle). The equipment is operatedat a pump speed between 5-18%, 100% aspirator, 40-42 mm nitrogenpressure and inlet air temperature ranged between 72-120° C. Thecollected spray dried product is sieved through a 90 μm screen beforefurther processing by roller compaction (method 2). The spray solutionwas composed of SNAC and nicotinamide (combined solid content rangingfrom 93-323 mg/mL).

Method 5: Spray Granulation

Spray granulation is carried out on a Mini-Glatt fluid bed using a topspray configuration (0.5 mm nozzle, 0.35 bar nozzle air pressure) withsatisfactory fluidisation air pressure and 40-50° C. process inlet airtemperature. In the initial batch process no solid charge is used andthe resulting product is collected and sieved through a 355 μm screen. Asecondary spray granulation batch process is carried out using thematerial collected from the initial batch process as starting materialand a post process drying in the equipment is carried out. The finalmaterial was sieved through a <500 μm screen. The spray solution wascomposed of SNAC and nicotinamide (combined solid content 500 mg/mL).

Method 6: Ball Milling

Ball milling is carried out either on a Fritsch pulverisette 6 planetaryball mill using a 250 mL zirconium oxide bowl and 55 (10 mm) agategrinding balls for up to 3 hours at 300 rpm. Cryo ball milling iscarried out on a Retsch MM200 ball mill with 10 mL stainless steelvessels and a single 20 mm stainless steel ball. The filled samplechamber is submerged in liquid nitrogen until the nitrogen stops boilingand subsequently milled for 15 min at 20 1/s, this process was repeatedfour times. For both milling methods the collected product is sievedthrough a 90 μm screen before further processing.

Method 7: Blending for Tablet Compression

Blending is carried out by manual geometric mixing the intermediategranulate with GLP-1 agonist followed by blending on a turbula mixer (7min, 25 rpm). In compositions including magnesium stearate or glyceryldibehenate it was sieved through a 125 μm or 355 μm mesh and added in asecondary blending step by manual geometric mixing followed by blendingon a turbula mixer (2 min, 25 rpm).

Method 8: Tablet Preparation

Tablets are produced on a Kilian Style One or a Fette 102I mounted witha single set of punches, resulting in 6.5 mm×11 mm, 7.2 mm×12 mm or 8.5mm×16 mm oval compound cup tablets having no score. Punch size is choseaccording to the total tablet weight. For the Kilian Style One the pressspeed is set to 10% and for Fette 102i the press speed is set at 20 rpm.The fill volume is adjusted to obtain tablets having target weightsbased on composition. Compression forces around 3 to 25 kN are appliedto obtain tablets with a crushing strength of around 20-120 N respectiveto the tablet size.

Example 1—Preparation of Compositions

Tablets with different amounts of GLP-1 agonist, SNAC and furtherexcipients were prepared. The content of the prepared compositions isprovided in Table 1 (Table 1.1, Table 1.2 and Table 1.3). GLP-1 agonistA is semaglutide, GLP-1 agonist B is Diacylated[Aib8,Arg34,Lys37]GLP-1(7-37) (Example 2 of WO2011/080103) and GLP-1agonist C isDiacylated-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly(Example 31 of WO2012/140117). Semaglutide can be prepared according tothe method described in WO2006/097537, Example 4. GLP-1 agonists B and Ccan be prepared as described in WO2011/080103 and WO2012/140117,respectively. SNAC was prepared according to the method described inWO2008/028859.

Reference compositions A, B and C were generally prepared as describedin WO2013/139694. The test compositions (A1, A2 and B2-B4, weregenerally prepared as described in method 1 and 2 above, with minorvariations in the process prior to roller compaction and tabletpreparation as specified below.

Example 2—Solid Compositions

Tablets with different amounts of GLP-1 agonist, SNAC and furtherexcipients were prepared. The content of the prepared compositions isprovided in Table 3 (Table 3.1 and Table 3.2).

Reference compositions A, B and C were generally prepared as describedin WO2013/139694.

The test composition B14 was prepared as described in method 5, 7 and 8above. The test compositions B11-13 and A3 were prepared as described inmethod 2, 4, 7 and 8 above.

The test compositions B1, B6-10, A1-2, and C1-C4 were generally preparedas described in method 3, 7 and 8 above, with minor variations in theprocess as specified below. Composition B1 was not sieved postextrusion; instead the extrudates were submerged in liquid nitrogen andreduced in particle size using a mortar and pestle. GLP-1 derivative wasadded into the mortar and co-ground to prepare the blend that wascompressed into tablets.

The test compositions B5 and B17 were generally prepared as described inmethod 1, 2, 7 and 8 above, with minor variations in the process asspecified below. SNAC (without resorcinol or nicotinamide) was blendedon a turbula mixer with 79.4% of the total magnesium stearate (30 min,25 rpm) and roller compacted according to method 2. Fines (<90 μm) wereremoved from the resulting granulate by sieving. In composition B5resorcinol was sieved through a 350 μm mesh prior to blending in method7. In composition B17 nicotinamide was sieved through a 315 μm meshprior to blending in method 7.

The test compositions B15-16 were generally prepared as described inmethod 2, 6, 7 and 8 above, with minor variations in the as process asspecified below. To prepare test compositions B15-16 the followingprocedure was followed; SNAC and nicotinamide were mixed by manualgeometric mixing followed by blending on a turbula mixer (7 min, 25rpm). The resulting blends were milled according to method 6 (B115 ballmilled & B16 cryo ball milled) followed by roller compaction asdescribed in method 1. The obtained granulates were further processedinto tablets according to method 7 and 8.

The test compositions B2-4 and B18-19 were generally prepared asdescribed in method 1, 2, 7, and 8 above, with minor variations in theprocess as specified below. To prepare test compositions B2-4 and B18-19the following procedure was followed; magnesium stearate was passedthrough a 355 μm or finer sieve. SNAC and nicotinamide (B18-B19) orresorcinol (B2-B4) were sieved <53 μm and the correct amounts ofexcipients was weighed off. The excipients were blended according tomethod 1 with the following variations. In composition B2 magnesiumstearate was added in the secondary blending step (62.5% of thecomposition, remainder was added in method 7. In composition B3magnesium stearate was added in the secondary blending step. Incomposition B18 62.5% of the total magnesium stearate was included(remainder was added in method 7) and blending time on the turbula mixerwas increased to 15 min. These blends were then roller compactedaccording to method 2 followed by preparation of the final tabletsaccording to method 7 and 8.

TABLE 3.1 Overview of compositions with GLP-1 agonist B GLP-1 MagnesiumGlyceryl agonist A SNAC Resorcinol Nicotinamide stearate dibehenatePovidone MCC Composition (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) B 5 300— — 9.7 — 8 80 B1 5 100 67 — 0 — — — B2 5 100 180 — 4.5 — — — B3 5 10061 — 2.5 — — — B4 5 300 180 — — 2.2 — — B5 5 300 180 — 9.7 — — — B6 5273 — 168 — 2.2 — — B7 5 100 — 61 — 0.8 — — B8 5 353 — 88 — 2.2 — — B9 5100 — 150 1.3 — — — B10 5 100 — 100 1 — — — B11 5 273 — 168 — 2.2 — —B12 5 100 — 180 3.2 — — — B13 5 100 — 60 1.6 — — — B14 5 100 — 67 0.8 —— — B15 5 100 — 67 — — — — B16 5 100 — 67 — — — — B17 5 300 — 540 9.7 —— — B18 5 100 — 180 4.5 — — — B19 5 273 — 168 — 2.2 — —

TABLE 3.2 Overview of compositions with GLP-1 agonist A GLP-1 Glycerylagonist SNAC Nicotinamide Magnesium dibehenate Povidone MCC CompositionB (mg) (mg) (mg) stearate (mg) (mg) (mg) (mg) A 3 300 — 9.7 — 8 80 A1 3273 168 — 2.2 A2 3 100  67 0.8 — A3 3 100  67 1.7 —

TABLE 3.3 Overview of compositions with GLP-1 agonist C GLP-1 MagnesiumCompo- agonist SNAC Nicotinamide stearate Povidone MCC sition C (mg)(mg) (mg) (mg) (mg) (mg) C 4 300 — 9.7 8 80 C1 4 100  67 0.8 — — C2 4274 182 2.4 — — C3 4 200 133 1.6 — — C4 4 100  25 0.8 — —

The exposure of the GLP-1 agonists was evaluated in a pharmacokineticstudy as described in Assay III demonstrating several folds increase(Table 4) in the dose corrected plasma concentrations of thecompositions comprising Resorcinol or Nicotinamide.

Table 4 Dose Corrected Exposures—Average Values

TABLE 4.1 Overview of compositions with GLP-1 agonist B Dose Dosecorrected AUC corrected 0-30 min exposure GLP-1 Formulation replicates(hr*kg/L) * t = 30 min agonist composition (n) 100) (kg/L) B Reference B24 3.16 0.17 B B1 16 13.38 0.50 B B2 16 10.06 0.42 B B3 16 14.86 0.61 BB4 16 14.99 0.64 B B5 8 9.98 0.44 B B6 16 13.5 0.66 B B7 16 15.99 0.72 BB8 16 8.35 0.45 B B9 16 13.2 0.55 B B10 14 10.10 0.40 B B11 16 12.160.62 B B12 16 11.26 0.46 B B13 15 11.85 0.49 B B14 16 12.64 0.53 B B1515 12.76 0.39 B B16 14 10.06 0.39 B B17 15 8.10 0.45 B B18 16 10.37 0.48B B19 11 8.69 0.40

TABLE 4.2 Overview of compositions with GLP-1 agonist A Dose Dosecorrected AUC corrected 0-30 min exposure GLP-1 Formulation replicates(hr*kg/L) * t = 30 min agonist composition (n) 100) (kg/L) A Reference A23 1.68 0.10 A A1 16 5.99 0.33 A A2 32 4.61 0.22 A A3 32 4.38 0.19

TABLE 4.3 Overview of compositions with GLP-1 agonist C Dose Dosecorrected AUC corrected 0-30 min exposure GLP-1 Formulation replicates(hr*kg/L) * t = 30 min agonist composition (n) 100) (kg/L) C C 64 4.050.23 C C1 48 12.59 0.49 C C2 31 13.42 0.63 C C3 16 11.45 0.54 C C4 1612.15 0.49

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

1. A composition comprising i) a GLP-1 agonist, ii) a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) and iii) a hydrotrope,wherein the hydrotrope is capable of increasing the solubility of SNACat least 5-fold or such as at least 10-fold.
 2. The compositionaccording to claim 1, wherein the hydrotrope is Nicotinamide orResorcinol.
 3. The composition according to claim 1, wherein the ratioof salt of NAC/hydrotrope (w/w) is 0.5-10, such as 0.5-8 or such as0.5-5.
 4. The composition according to claim 1, wherein the compositionfurther comprising a lubricant selected from magnesium stearate andglyceryl dibehenate.
 5. The composition according to claim 1, whereinthe GLP-1 agonist comprises at least one albumin binding substituent. 6.The composition according to claim 1, wherein the GLP-1 agonist isselected from the group consisting of: liraglutide, semaglutide, GLP-1agonist B and GLP-1 agonist C.
 7. The composition according to claim 1,wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) isthe sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC). 8.The composition according to claim 1, wherein the composition is a solidcomposition.
 9. The composition according to claim 1 consisting of: i) aGLP-1 agonist ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid(NAC) iii) nicotinamide or resorcinol and iv) a lubricant.
 10. Thecomposition according to claim 1, wherein a unit dosage comprises i)0.1-30 mg, such as 0.1-20 mg GLP-1 agonist, such as Semaglutide, GLP-1agonist B or GLP-1 agonist C. ii) 50-600 mg salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), such as the sodiumsalt of NAC (SNAC) and iii) 20-200 mg nicotinamide iv) 0-10 mglubricant.
 11. The composition according to claim 1, wherein thecomposition is a pharmaceutical composition for oral administration. 12.The composition according to claim 1, wherein the composition is apharmaceutical composition for use in a method of treating diabetesand/or obesity.
 13. A method for producing a solid pharmaceuticalcomposition comprising the steps of; i) obtaining a blend comprising asalt of NAC and a hydrotrope, ii) co-processing the blend of i) and iii)preparing said solid pharmaceutical composition using the product ofii).
 14. A method for producing a solid pharmaceutical compositioncomprising the steps of; i) obtaining a blend comprising a salt of NACand a hydrotrope, ii) heat melt extruding the blend of i), iii) millingthe extrudate of ii) and iv) preparing said solid pharmaceuticalcomposition using the product of iii).
 15. A method for producing asolid pharmaceutical composition comprising the steps of i) obtaining ablend comprising a salt of NAC and a hydrotrope, ii) heat melt extrudingthe blend of i), iii) admixing the extrudate of ii) with an activepharmaceutical ingredient and optionally any further excipients and iv)preparing said solid pharmaceutical composition using the mixture ofiii).